Pathogen-tailored role of interferon-λs in neutrophil function during fungal immunity 2235

Abstract Description Aspergillus fumigatus (Af), a ubiquitous airborne fungus, is responsible for more than 90% invasive aspergillosis (IA) cases. Af infections are treated with triazole antifungals. However, these treatments are becoming less effective as Af strains develop resistance. Neutrophils play a crucial role in innate defense against Af. Type I interferons (IFN-I) induce the early production of interferon-lambda (IFN-λ), which controls neutrophil antifungal activity. However, the mechanisms through which IFN-λ modulates neutrophil effector function beyond ROS remain unexplored. We hypothesize that neutrophil-produced IFN-λ is essential for antifungal responses by regulating ISG expression in an autocrine manner. To explore this, we conducted bulk RNA-seq on neutrophils isolated from the lungs of naïve, wild-type (WT), IFNAR-/-, IFNLR-/-, and double knockout (IFNAR-/- IFNLR-/-) mouse models after 48 hours of Aspergillus infection. WT neutrophils exhibited significant upregulation of ISGs, including Oas1, Irf7, Ifit1, Isg15, and Cmpk2, all of which were downregulated in in IFNLR-/- and double knockout cells. We also identified the expression of IFNLR and IFN-λ2/3 in bone marrow neutrophils following Af stimulation. Using phosphoflow, we assess STAT1 activation during neutrophil maturation in response to Af, focusing on STAT1-dependent pathways in IFN-λ-mediated responses. Our findings indicate that IFN-λ is crucial for modulating neutrophil responses to Af via ISGs regulation. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)